There is increasing evidence that infections and vaccinations play an important role in the normal maturation of the immune system. It was therefore of interest to determine whether these immune events also affect the prognosis of melanoma patients. A cohort study of 542 melanoma patients in six European countries and Israel was conducted. Patients were followed up for a mean of 5 years and overall survival was recorded. Biometric evaluations included Kaplan-Meier estimates of survival over time and Hazard Ratios (HRs), taking into account all known prognostic factors. During the follow-up between 1993 and 2002, 182 of the 542 patients (34%) died. Survival curves, related to Breslow's thickness as the most important prognostic marker, were in accordance with those observed in previous studies where the cause of death was known to be due to disseminated melanoma. In a separate analysis of patients, vaccinated with vaccinia or Bacille Calmette-Guérin (BCG), HRs and the corresponding 95% Confidence Intervals (CIs) were 0.52 (0.34-0.79) and 0.69 (0.49-0.98), respectively. Joint analyses yielded HRs (and 95% CIs) of 0.55 (0.34-0.89) for patients vaccinated with vaccinia, 0.75 (0.30-1.86) with BCG, and 0.41 (0.25-0.69) with both vaccines. In contrast, infectious diseases occurring before the excision of the tumour had little, or, at the most, a minor influence on the outcome of the melanoma patients. These data reveal, for the first time, that vaccination with vaccinia in early life significantly prolongs the survival of patients with a malignant tumour after initial surgical management. BCG vaccination seems to have a similar, although weaker, effect. The underlying immune mechanisms involved remain to be determined.